Optimized EGFR Blockade Strategies in <i>EGFR</i> Addicted Gastroesophageal Adenocarcinomas.

Abstract

Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents. We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX). The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that <i>EGFR</i> amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with <i>EGFR</i> copy-number gain and that coamplification of other receptor tyrosine kinases or <i>KRAS</i> is associated with worse response. Preclinical trials performed on <i>EGFR</i>-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly <i>EGFR-</i>amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the <i>TSC2</i> tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition. This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors.<i>See related commentary by Openshaw et al., p. 2964</i>.